Chemotherapy remains the primary treatment for advanced lung squamous cell carcinoma (LUSC); however, its severe toxic side effects significantly limit therapeutic efficacy. There is an urgent clinical need to integrate molecular targeting with chemotherapy to enhance treatment outcomes. Consequently, this study developed a co-loaded albumin-based nanodelivery system (NLB/PTX-NPs) for targeted delivery of nilotinib alongside the chemotherapeutic agent paclitaxel. We systematically evaluated its in vitro and in vivo anti-tumor activity, safety, and underlying molecular mechanisms. NLB/PTX-NPs were synthesized via the solvent displacement method, followed by characterization of their physicochemical properties, drug-loading performance, and biosafety. Using NCI-H520 cells as a model, the in vitro efficacy and molecular mechanisms were evaluated through cellular uptake studies, cytotoxicity assessments, in vitro cellular experiments, and Western Blot assays. Additionally, subcutaneous tumor and lung metastasis models were established in nude mice to evaluate in vivo targeted distribution, as well as anti-tumor and anti-metastatic activities. NLB/PTX-NPs exhibited a uniform spherical morphology, demonstrating excellent dispersibility, stability, and biosafety. In vitro experiments revealed that the nanoparticles significantly enhanced cellular uptake and inhibited the proliferation, migration, and invasion of NCI-H520 cells. Western blot analysis confirmed their ability to regulate the expression of proteins associated with apoptosis and epithelial-mesenchymal transition (EMT). Furthermore, in vivo experiments indicated that the nanoparticles significantly accumulated in tumor tissues, synergistically inhibiting tumor growth (P < 0.001) and lung metastasis (P < 0.05) through the downregulation of NF-κB and IKBα phosphorylation levels, as well as a reduction in the Ki67 index, without any apparent systemic toxicity. This study successfully developed NLB/PTX-NPs, achieving effective co-loading of dual drugs, efficient enrichment, and synergistic delivery at tumor sites. The system demonstrated promising preclinical anti-tumor and anti-metastatic effects in the NCI-H520 models by synergistically inhibiting the NF-κB pathway, thereby providing a novel strategy for the treatment of lung squamous cell carcinoma.

Cancer persists as a significant global health burden, with conventional therapeutic approaches frequently constrained by drug resistance and disease relapse, underscoring the urgent requirement for innovative treatment modalities. Recent advances in regulated cell death have uncovered promising therapeutic avenues for cancer. Amidst these newly identified processes, disulfidptosis-a distinct type of programmed cell death triggered by disulfide stress-has garnered significant attention because of its specific metabolic reliance. The underlying mechanism centers on pathological intracellular cystine accumulation coupled with depletion of NADPH reducing equivalents, stemming from elevated levels of the cystine transporter SLC7A11 during metabolic stress states such as glucose deprivation. This cascade induces aberrant disulfide bonding followed by actin cytoskeleton disruption, ultimately resulting in cellular demise. Evidence suggests that disulfidptosis-related genes exhibit altered expression across various malignancies, including lung, liver, and colorectal cancers, and are strongly correlated with disease progression and patient outcomes. Prognostic models constructed based on bioinformatics not only demonstrate good predictive efficacy but also reflect characteristics of the tumor immune microenvironment. This process reveals a fundamental weakness in cancer cells after metabolic reprogramming, establishing the induction of disulfidptosis via SLC7A11 inhibition or modulation of associated metabolic pathways as a promising new anticancer approach. It also provides a rationale for combination strategies with chemotherapy, targeted therapy, and immunotherapy. Nonetheless, its interaction with different cell death mechanisms (including ferroptosis), the variability observed across various cancer types, and the translation to clinical applications remain significant challenges and key avenues for future investigation.

mTOR inhibitors including everolimus and temsirolimus have been approved by US FDA for treatment of clear cell renal cell carcinoma (ccRCC) in clinic. However, resistance to these drugs has been inevitable and the underlying mechanism remains poorly understood. Histone modifier ZMYND8 paradoxically acts as a transcription coactivator or corepressor. Here we show that SPOP, a CULLIN3-RING E3 ubiquitin ligase (CRL) substrate-binding protein that is often overexpressed in ccRCC in patients, promotes K63-linked polyubiquitination of ZMYND8 at lysine 398, which inhibits ZMYND8 to form phase separation compartments and drives the formation of ZMYND8-ZHX2 transactivation complex, resulting in aberrant NEK7 kinase gene transcription, alternative activation of p70S6K, and mTOR inhibitor-resistant cell growth. Inhibition of either SPOP or NEK7 increases ccRCC cell sensitivity to mTOR inhibitor. Treatment with a NEK7 proteolysis-targeting chimera (PROTAC) effectively inhibits aberrant p70S6K activation and overcame everolimus resistance in ccRCC cells in vitro and in mice. Our findings uncover a function switch of ZMYND8 driven by overexpressed SPOP as a key mechanism that causes mTOR inhibitor resistance and nominate NEK7 as a potential target of thwarting mTOR inhibitor resistance in ccRCC.

Despite effective therapies such as proteasome inhibitors, multiple myeloma (MM) patients relapse with refractory disease. Analysis of RNA sequencing data from CD138 + MM patient cells (n = 813) across disease stages identifies an autophagy gene signature. Particularly elevated ULK3 expression is strongly associated with disease progression. Functional studies reveal that ULK3 supports MM cell survival via the ULK-ATG13-FIP200 complex. We generate small-molecule kinase inhibitors (SG3-014/MA9-060) exhibiting nanomolar potency against ULK3, with binding confirmed by co-crystallization. While exhibiting multikinase activity, pharmacologic targeting reduces MM burden in vivo, improves survival, and mitigates MM-associated bone disease. Here, we also show that MA9-060 enhances sensitivity to proteasome inhibitors in resistant MM cells, with effects confirmed ex vivo in primary patient samples, particularly those with high ULK3 expression. These findings implicate ULK3-associated autophagy in MM progression and support further evaluation of ULK3-directed kinase inhibition as a therapeutic strategy in newly diagnosed and refractory MM.

Cancer heterogeneity drives therapeutic failure, resistance, and relapse and encompasses variation across genetic, cellular, tissue, organ, and systemic scales. Existing frameworks define malignant capabilities and tumor-microenvironment interactions but less explicitly address how heterogeneity propagates across scales and informs therapeutic design. Here, we propose the Holistic Integrative Tumor Ecosystem Theory (HITET), a five-dimensional framework connecting these scales through functional interfaces. Its organizing principle is the niche-flow-feedback triad: niches define selective habitats; flows transmit cells, resources, and signals across scales; and feedback loops amplify or constrain heterogeneity by reshaping niches and flows. HITET generates several provisional predictions: interventions targeting three or more active dimensions may produce more durable responses than narrower strategies; tumors with strong vascular-immune coupling may be particularly sensitive to combined vascular normalization and immune activation; and clonal or phenotypic diversification may correlate with the number and strength of positive feedback loops. We use HITET to synthesize how genetic alterations, cellular plasticity, metabolic programs, immune and stromal interactions, spatial gradients, organ-specific environments, microbiota, and host physiology jointly shape cancer heterogeneity. Therapeutically, HITET organizes strategies as vertical integration within a dimension, horizontal integration across dimensions, and modulation of host-tumor interfaces. HITET does not replace existing cancer frameworks or constitute a validated predictive model. Its current contribution is organizational and hypothesis-generating, providing a structured basis for linking mechanisms and measurements and developing predictions that require prospective experimental and clinical validation.

Targeting synthetic lethal interactions has emerged as a promising strategy for cancer therapeutics, particularly by exploiting DNA damage response (DDR) pathways. A well-known example of this are PARP inhibitors, that selectively kill cancer cells compromised by mutations in DDR genes like BRCA1/2, while sparing normal cells with functional homologous recombination repair. These compounds have substantially improved clinical outcomes, especially in BRCA1/2-mutated ovarian cancer, enhancing both survival rates and quality of life. Their great clinical impact has been constrained by the appearance of resistance and safety concerns. New generation PARP inhibitors are being developed with enhanced selectivity and reduced side effects. Beyond PARP inhibition, several other drugs inhibiting key DDR components, such as ATR, ATM and DNA-PK, have progressed to clinical trials. These DDR inhibitors are being studied alone or in combination with chemotherapy, radiotherapy, immunotherapy or other targeted therapy, increasing efficacy and improving outcomes in resistant and advanced cancers. While most synthetic lethality-based clinical trials in oncology target DDR, an increasing trend in the preclinical and clinical setting is focused on inhibiting non-DDR pathways (e.g., PRMT5 and SMARCA4/2). However, challenges remain in determining the most effective combinations, identifying which patient populations will benefit the most from these therapies and overcoming resistance. Continued research is also essential to fully understand the intricate network of synthetic lethality and maximize the therapeutic potential of synthetic lethality-based therapies. Nonetheless, targeting synthetic lethal interactions with inhibitors represents an exciting frontier in precision oncology, offering the potential for more tailored, effective and less toxic cancer treatments.

Antibody-drug conjugates (ADCs) represent a rapidly expanding class of targeted cancer therapeutics that combine the high selectivity of monoclonal antibodies with the potent cytotoxic activity of small-molecule drugs. Their clinical success relies on the simultaneous optimization of multiple interdependent parameters, including antigen selection, antibody engineering, linker chemistry, and payload pharmacology, which limits the effectiveness of traditional empirical approaches. In this context, recent advances in artificial intelligence (AI) and computational biophysics are transforming the rational design of ADCs. AI enables large-scale integration of genomic, transcriptomic, and proteomic data to identify tumor-selective, surface-accessible antigens and to support patient stratification strategies. Deep learning models enhance antibody engineering by predicting structure, affinity, stability, and developability, while generative algorithms accelerate affinity maturation and specificity optimization. Computational prediction of linker design and conjugation sites improves plasma stability, controlled payload release, and drug-to-antibody ratio, whereas graph-based neural networks facilitate the selection and optimization of cytotoxic payloads with favorable potency, membrane permeability, and bystander effects. Complementary molecular dynamics simulations provide atomistic insight into antibody conformation, linker flexibility, and payload interactions, enabling a deeper mechanistic understanding of ADC stability and function. At the translational level, hybrid physiologically based pharmacokinetic-AI models and digital twin simulations enable virtual evaluation of tumor penetration, systemic exposure and safety, ultimately supporting dose optimization and more efficient clinical development. Although this review places particular emphasis on the application of these approaches in oncology, emerging ADC strategies beyond cancer-including autoimmune, neurodegenerative, cardiovascular, and metabolic diseases-are also discussed. Together, these computational strategies represent a convergence of machine intelligence and molecular biology that is poised to fundamentally transform ADC development, enabling safer, more precise, and effective therapies across oncology and beyond.

The acid-sensing ion channel 3 (ASIC3) is a neuronal voltage-insensitive Na⁺ channel located in the peripheral nervous system (PNS) and activated by extracellular H⁺, that is dysregulated in peripheral neuropathic pain. ASIC3 was found in stem cells of central nervous system (CNS)-located glioblastoma multiforme (GBM CSCs), and its chronic activation kills dysfunctional GBM CSCs without any effect on ASIC3-lacking CNS tissues. We rationally designed and synthesized blood-brain barrier (BBB)-compliant analogues of GMQ, a known guanidyl quinazoline ASIC3 activator; we replaced its guanidine group with a guanyl hydrazone (GH) and carried out scaffold substitutions and other structural variations in 16 GMQ analogues to establish a structure-activity relationship (SAR). Our more potent GH analogue 1a showed specific activity against GBM CSC neurospheres, coupled with a better safety profile on mammalian nontumor cells and a better brain-to-plasma ratio compared with GMQ. Such results provide valuable insights for further structural optimization of heteroaryl GHs as ASIC3 modulators.

Ghost cell odontogenic carcinoma (GCOC) is an exceptionally rare malignant odontogenic neoplasm representing the aggressive end of the calcifying cystic odontogenic tumor spectrum, with fewer than 50 well-characterized cases reported in the English-language literature and a marked predilection for Asian males in the fifth to seventh decades of life. A 38-year-old African American female presented with an expansile anterior mandibular radiolucency initially misdiagnosed as mandibular tori, then as a calcifying odontogenic cyst on incisional biopsy; progressive neurological symptoms and lesion growth prompted definitive surgical resection. Final histopathologic examination revealed infiltrating odontogenic epithelium with ameloblastoma-like features, cellular atypia, increased mitotic activity, ghost cell populations, and vascular invasion. Immunohistochemistry demonstrated an elevated Ki-67 index and β-catenin nuclear reactivity, confirming the diagnosis of GCOC, and postoperative PET scan showed no distant metastatic disease. This case represents a significant epidemiological departure from established GCOC demographics and underscores the importance of correlating clinical, radiographic, histopathologic, and immunohistochemical findings to reach an accurate diagnosis, highlighting the necessity of a multidisciplinary approach for optimal management of this rare malignancy.

The objective of this study was to evaluate the effectiveness and safety of pembrolizumab as monotherapy in patients with Non-Small-Cell Lung Cancer and brain metastases in Real-World clinical practice at Tertiary care.

A retrospective observational study was conducted at a tertiary hospital in Spain between August 2017 and March 2023. Adult patients with stage IV non-small-cell lung carcinoma and radiologically confirmed brain metastases who received pembrolizumab monotherapy were included. Progression-free survival, overall survival, objective response rate and treatment-related adverse events were analyzed.

Among 172 patients treated with pembrolizumab, 45 had brain metastases and 25 received monotherapy. Median progression-free survival was 3 months (95% confidence interval: 2.02-3.97), and median overall survival was 6 months (95% confidence interval: 4.37-7.62). The objective response rate was 24%, and the disease control rate was 40%. Treatment-related toxicity of any grade was reported in 64% of patients, with no unexpected safety signals observed.

Pembrolizumab monotherapy showed clinical activity and an acceptable safety profile in patients with non-small-cell lung carcinoma and brain metastases treated in routine practice. Larger prospective studies are needed to optimize patient selection in this setting.